A metabolome-wide analysis of Intraocular pressure suggests neuroinflammatory mechanisms as possible mechanisms involved in glaucoma

Abstract

Purpose : Although glaucoma is associated with cardiometabolic disease, mechanisms linking metabolism to glaucomatous optic neuropathy are not well understood. Oxidative stress and fatty acid have been implicated, but the relatively small scale of previous studies impeded a good understanding of the metabolic basis of glaucoma. This study aimed to better understand the association of peripherally circulating metabolite levels with intraocular pressure, a strong glaucoma risk factor.

Methods : Analyses were conducted using plasma levels of 1458 metabolites, measured in 9909 subjects of European ancestry (4614 female and 4485 male) who participated in the Canadian Longitudinal Study of Ageing (CLSA). The relationship between metabolites and corneal-compensated IOP was explored through feature selection random forest (RF) analyses on both the whole sample and sex-stratified. Results were replicated through regression modeling in a sample of 1562 female participants in the TwinsUK cohort.

Results : The analyses confirmed the importance of previously reported ascorbic acid metabolites in IOP homeostasis. In addition, cortolone glucuronide, a glucocorticoid hormone, ranked top among the metabolites influencing IOP in the mixed sex analyses. Because importance rankings showed a high degree of sex-related heterogeneity, we carried forward the 10 highest-ranked metabolites from each analysis and tested them for linear associations with IOP in an independent, albeit female, cohort. Among metabolites available for replication, the strongest association was found for 3-hydroxylaurate (p=0.026 after Bonferroni). This metabolite is a powerful agonist of GPR84, a pro-neuroinflammatory protein that participates in glial inflammatory response following nerve damage. Previous murine models have also implicated it in ganglion cell loss after optic nerve trauma. Causal inference analyses however did not support causality in the relationship of this metabolite and IOP.

Conclusions : This study identified new metabolites that are likely to participate in mechanisms regulating IOP in the general population. Notwithstanding ethnicity, sample size and sex imbalance limitations, these results suggest specific molecular mechanisms linking metabolism with IOP and glaucoma, whose validity will await confirmation from future studies.

This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.

 

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